Skin reactions to tyrosine kinase inhibitors in pediatric patients with chronic myeloid leukemia.

Cutaneous adverse events are commonly reported in adult patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs); however, little is known about the cutaneous reactions in children receiving TKIs for CML. As pediatric patients may require lifelong TKI therapy, it is essential to understand the wide range of potential cutaneous toxicities. We examined all case studies, cohort studies, and clinical trials in PubMed/MEDLINE and Embase that reported cutaneous reactions to first-, second-, and third-generation TKIs in children 18 years or younger with CML. This review article focuses on the TKI drug types and doses, patient demographic characteristics, features of skin reactions, and clinical outcomes.

Distinct skin microbiome community structures in congenital ichthyosis.

BACKGROUND: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. OBJECTIVES: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. METHODS: Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. RESULTS: Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. CONCLUSIONS: The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.

Transepidermal water loss in the orphan forms of ichthyosis.

As a surrogate measure of skin barrier dysfunction, we sought to determine differences in transepidermal water loss (TEWL) among ichthyosis subtypes and correlate TEWL with clinical severity. Subjects with Netherton syndrome had the highest TEWL values (increased water loss), while TEWL values were lowest in subjects with epidermolytic ichthyosis. TEWL correlated with severity only in lamellar ichthyosis and age was inversely correlated with TEWL (rs  = -.213, P = .02). TEWL is an objective measure that complements disease severity in ichthyosis and may be used as an adjuvant to monitor treatment response.

Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center.

BACKGROUND: Sweet syndrome is a neutrophilic dermatosis that may be categorized into classic, malignancy-associated, and drug-induced subtypes. Few studies have systematically analyzed this rare disorder. OBJECTIVE: To describe the clinicopathologic characteristics and treatment of Sweet syndrome and identify characteristics associated with concurrent malignancy. METHODS: We retrospectively reviewed patients with Sweet syndrome at the University of Pennsylvania from 2005 to 2015. RESULTS: We identified 83 patients (mean age, 57 years; 51% male) with Sweet syndrome: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. Acute myeloid leukemia was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia (P < .001), anemia (P = .002), thrombocytopenia (P < .001), absence of arthralgia (P < .001), and histiocytoid or subcutaneous histopathology (P = .024) were associated with malignancy (χ2 test). LIMITATIONS: This was a retrospective study that represents patients from a single tertiary academic referral center, which may limit its generalizability to other settings. CONCLUSION: When caring for patients with Sweet syndrome, dermatologists should be aware of the potential association of leukopenia, anemia, thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology with malignancy.

Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition.

Bacterial infections can quickly turn into sepsis, with its attendant clinical sequelae of inflammation, tissue injury, and organ failure. Paradoxically, sustained inflammation in sepsis may lead to immune suppression, because of which the host is unable to clear the existing infection. Use of agents that suppress the inflammatory response may accelerate host immune suppression, whereas use of traditional antibiotics does not significantly affect inflammation. In this study, we investigated whether lipoxin A4 (LXA4), a specialized, proresolution lipid mediator, could increase neutrophil phagocytic activity as well as reduce bacterial virulence. Using the mouse cecal ligation and puncture (CLP) model of sepsis, the administration of LXA4 (7 µg/kg i.v.) 1 h after surgery increased neutrophil phagocytic ability and Fcγ receptor I (CD64) expression. Ex vivo studies have confirmed that the direct addition of LXA4 to CLP neutrophils increased phagocytic ability but not CD64 expression. LXA4 did not affect neutrophils taken from control mice in which CD64 expression was minimal. Taken together with in vivo data, these results suggest that LXA4 directly augments CD64-mediated neutrophil phagocytic ability but does not directly increase neutrophil CD64 expression. Bacterial communication and virulence is regulated by quorum sensing inducers. In Pseudomonas aeruginosa, virulence is induced with release of various virulence factors, by N-3-oxododecanolyl homoserine lactone binding to the quorum sensing receptor, LasR. We show that LXA4 is an inhibitor of LasR in P. aeruginosa and that it decreases the release of pyocyanin exotoxin. These results suggest that LXA4 has the novel dual properties of increasing host defense and decreasing pathogen virulence by inhibiting quorum sensing.-Wu, B., Capilato, J., Pham, M. P., Walker, J., Spur, B., Rodriguez, A., Perez, L. J., Yin, K. Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition.

Majocchi Granuloma Superinfected With Herpes Zoster.

Herpes zoster (HZ) infection is caused by the reactivation of the varicella-zoster virus (VZV) and has very rarely been reported at the site of a superficial fungal infection. Also, HZ occurring at the site of a deep fungal infection has not been reported in the literature. We discuss a unique case of a 45-year-old male patient presenting with a Majocchi granuloma (MG) superinfected with disseminated HZ.

Human Inborn Errors of Immunity in Pyoderma Gangrenosum: A Systematic Review.

BACKGROUND AND OBJECTIVE: Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that can be associated with primary immunodeficiency. The pathogenesis of PG has not yet been elucidated, although contributions from dysregulation of the immune system in patients with apparent genetic predispositions have been postulated. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review with the objective of identifying inborn errors of immunity in the presence of PG as well as their clinical characteristics of severity including number of PG lesions and anatomic areas affected, and treatment outcomes. METHODS: A literature search was performed using PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science through August 24, 2023, for studies published in English using the search terms: "pyoderma gangrenosum," "inborn error of immunity," "immune defect*," and a list of genetic mutations potentially associated with PG. RESULTS: Seventy-four cases of PG associated with inborn errors of immunity were identified. The results demonstrate an association of PG with a variety of inborn errors of immunity, including genetic mutations not classically associated with the condition. Genetic mutations such as BTK, IL1RN, ITGB2, LPIN2, MEFV, NFkB1, NLRP3, NLRP12, NOD2, PSMB8, PLCG2, PSTPIP1, RAG1, TTC37, and WDR1, as well as complement component 2/complement component 4 (C2/C4) and complement component 7 (C7) deficiencies were identified in the presence of either idiopathic or syndromic PG. Of note, mutations in genes such as PSMB8, NLRP3, and IL1RN were found to be associated with a more severe and atypical course of PG, whereas mutations in RAG1 as well as those causing a C2/C4 deficiency were associated with the mildest clinical presentations of PG. Mutations in NFkB1, ITGB2, and PSTPIP1 were associated with the most heterogeneous clinical presentations. CONCLUSIONS: Human inborn errors of immunity may be implicated in the genetic predisposition to PG and may influence the clinical presentation. Due to the rarity of these diseases, further work must be done to describe the association between inborn errors of immunity and PG. Identifying inborn errors of immunity that may contribute to the development of PG may assist in further elucidating the mechanism of PG, guiding targeted treatment, and improving clinical outcomes for these patients.

Violaceous nodules of the extensor joints - a clinicopathological challenge.

Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a condition characterized by vessel inflammation and may have a variety of etiologies. Among these, cocaine and its common adulterant, levamisole, have been described to contribute to the development of AAV with distinct cutaneous manifestations. Classically, these manifestations involve purpuric or necrotic lesions involving the ears, nose, and extremities. However, we present a case of cocaine-induced AAV presenting with violaceous nodules on the dorsal hands in order to demonstrate that this condition may not always present with retiform purpura and skin necrosis.

Secukinumab responses vary across the spectrum of congenital ichthyosis in adults.

IMPORTANCE: Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity. OBJECTIVE: To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes. DESIGN: Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively. SETTING: Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York. PARTICIPANTS: Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma. RESULTS: IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29-50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels. LIMITATIONS: Small sample size; heterogeneous ichthyosis subsets. CONCLUSION: IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses. GOV REGISTRATION NUMBER: NCT03041038; first posted on 02/02/2017.